The immunological architecture of granulomatous inflammation in central nervous system tuberculosis

Stefan-Dan Zaharie, Daniel J. Franken, Martijn van der Kuip, Sabine van Elsland, Bernadette S. de Bakker, Jaco Hagoort, Sanna L. Roest, Carmen S. van Dam, Carlie Timmers, Regan Solomons, Ronald van Toorn, Mariana Kruger, A. Marceline van Furth

Research output: Contribution to journalArticleAcademicpeer-review


Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.

Original languageEnglish
Article number102016
Pages (from-to)102016
Publication statusPublished - Dec 2020

Cite this